Cell Death Pathways in Diseases and Treatment of Lymphohematopoietic Tumors

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Abstract • 177

Homeostasis in the hemapoietic system is tightly regulated by cellular programs which control proliferation or apoptosis. Apoptosis may be induced by cellular receptors and activation of signal transduction pathways. One of the best studied systems in the CD95 (APO-1/FAS) system which belong to the TNF/NGF receptor superfamily of cell surface molecules. CD95 is widely expressed in lymphohematopoietic cells and CD95 ligand (CD95L) can be induced in almost all hematopoietic cells by appropriate stimuli e.g. T cell receptor triggering or cytokines. Defects in the CD95 system lead to a profound pathology with accumulation of polyclonal T cells leading to lymphoproliferation and an autoimmunity syndrome (autoimmune lymphoproliferative syndrome, ALPS). In ALPS and some hemapoietic malignancies CD95 mutations are found that are mainly clustered in the intracellular adaptor domain of the receptor. Following multimerization of the receptor a signal transduction pathway is initiated which leads to activation of caspases as apoptosis effector molecules. Activation induced cell death in T cells is mediated by activation induced triggering of CD95L/receptor interaction. Following CD95L/receptor interaction a death inducing signaling complex (DISC) is formed which contains the adaptor molecule FADD and the receptor proximate caspase FLICE in addition to the ligand/receptor complex. Increased CD95L/receptor interaction also appears to play a crucial role in diseases of hemapoietic cells such as aplastic anemia and HIV infection. Triggering of CD95L/ receptor interaction and activation of the CD95 pathway also appears to be an important mechanism for cytotoxicity mediated by anticancer drugs at least in some cells. CD95 resistant cells exhibit crossresistance towards drug induced apoptosis and inhibition of CD95L/receptor interaction may decrease the effectiveness of drug treatment of leukemic cell lines in vitro. In addition to CD95L/receptor interaction perturbance of mitochondrial function appears to be a key event in drug induced apoptosis. In addition, inhibition of drug induced cytotoxicity by Bcl-2 seems to operate at the level of inhibition of mitochondrial release of apoptogenic factors as cytochrome c and apoptosis inducing factor (AIF). The discovery of the involvement of physiological apoptosis pathways in drug induced cytotoxicity establishes a new molecular understanding of sensitivity and resistance of tumor cells against antineoplastic treatment and may help to develop new antitumor agents.

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Debatin, K. Cell Death Pathways in Diseases and Treatment of Lymphohematopoietic Tumors. Pediatr Res 45, 772 (1999) doi:10.1203/00006450-199905010-00207

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